In this issue of the Bulletin, three linked analyses of
antipsychotic prescribing practice are published
(Lelliott et al, 2002;
Harrington et al,
2002a,
b). The main findings
of these studies are that high-dose prescribing and polypharmacy were
commonplace at the time of the study and that generally patients were neither
properly informed nor appropriately monitored. High-dose prescribing seemed to
be strongly associated with polypharmacy — a practice for which there
was a substantial variation in frequency between study centres.

Many will say that these studies merely quantify what is already known:
that antipsychotic prescribing is less than perfect by evidence-based
standards and that practice varies substantially according to patient,
prescriber and institution. Nevertheless, the predictability of the findings
of these studies should not detract from their importance. Nor should it
prevent us from examining carefully the justification for prescribing drugs in
a way which bears only a passing resemblance to the way in which they were
used in efficacy studies establishing their worth.

Is ‘high-dose’ treatment better than ‘low-dose’?
Are two antipsychotics better than one? We don't know. There has been a
surprisingly large number of high-dose trials conducted, but very few meet
today's exacting standards for properly conducted studies. The only conclusion
that can be drawn from these data is that a minority of patients may benefit
from high doses (Aubree & Lader,
1980). Against this is the observation that, in recent
dose-finding studies of atypical drugs, there appears to be a threshold
effect. That is, above a certain dose limit all doses give rise to the same
degree of response (risperidone and quetiapine are good examples). This
threshold theory is supported by recent neuroimaging studies
(Kapur et al,
2000).

Polypharmacy of antipsychotics is probably even less well supported
(Davidson, 1974;
Godleski et al, 1989),
with very few available to suggest that two drugs are effective where one
alone is not (Yuzda, 2000).
The only exception is that of augmenting response to clozapine. This has the
backing of some clinical trials and is difficult to argue against in the
context of poor response to clozapine alone
(Canales et al,
1999).

Is ‘high-dose’ treatment safe? Probably not. Many
antipsychotics prolong the cardiac QT interval (in a dose-dependent fashion)
and may cause torsade de pointes and sudden death
(Glassman & Bigger, 2001).
Even moderate (but not low) doses of typical antipsychotics appear to increase
the risk of sudden death (Ray et
al, 2001).

Polypharmacy of antipsychotics also has clear adverse consequences. Most
seriously, it has been suggested that polypharmacy is associated in some way
with early death (Waddington et
al, 1998). In addition, the co-prescription of typical
antipsychotics with atypical drugs has been shown to increase the frequency of
acute extrapyramidal side-effects to levels expected when typicals are used
alone (Taylor et al,
1997,
2000). Presumably the risks of
tardive dyskinesia and hyperprolactinaemia are similarly increased. Apart from
this, there is very probably an important risk of adverse interaction when
antipsychotics are prescribed together, either through inhibition of
metabolism or through summation of toxic effects (such as QT
prolongation).

Overall, the practices of high-dose prescribing and antipsychotic
polypharmacy seem unsupportable — somewhat feeble evidence supports any
therapeutic benefit, while rather more robust evidence suggests adverse
consequences. Why, then, do these practices continue? It is possible, of
course, that for some patients two antipsychotics are more effective than one.
It may be that clinical trials are unable to detect subtle but important
improvements seen in patients receiving high-dose treatment. It may also be
true that different antipsychotics are prescribed together because they have
different effects on different symptoms of psychosis. Thus, polypharmcy may
represent the optimal application of scientific knowledge and clinical
experience combined.

In considering these possibilities, it would be unwise to suggest that
high-dose prescribing and polypharmacy should always be avoided and always be
viewed as poor prescribing. None the less, given the known and suspected
adverse consequences of these practices, it does seem sensible to restrict
such prescribing to patients in whom usual dose, single-drug prescribing has
been satisfactorily proven to be inadequate. Recent observational studies
suggest that physicians are too ready to resort to polypharmacy
(Taylor et al,
2002a) and that it is used ineffectually where the use of
clozapine might be a better option (Taylor
et al, 2002b). More recently still, the National
Institute for Clinical Excellence (NICE,
2002) has endorsed this viewpoint by recommending that
‘
atypical and typical antipsychotics should not be prescribed
concurrently’.

The introduction of atypical antipsychotics has, to some extent, encouraged
a more scientific approach to the treatment of schizophrenia. It is to be
hoped that this will eventually result in poorly supported, unsafe practice
being abandoned except where there is very clear evidence of patient benefit.
This is certainly the time to review prescribing practices in schizophrenia
and other psychoses and to move towards a more evidence-based approach.

TAYLOR, D., MACE, S., MIR, S., et al (2000) A
prescription survey of the use of atypical antipsychotics for hospital
inpatients in the United Kingdom. International Journal of
Psychiatry in Clinical Practice, 4,
41
-46.